{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,26]],"date-time":"2026-10-26T19:21:41Z","timestamp":1793042501599,"version":"4.5.0"},"reference-count":56,"publisher":"National Academy of Sciences","issue":"19","license":[{"start":{"date-parts":[[2016,4,25]],"date-time":"2016-04-25T00:00:00Z","timestamp":1461542400000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/www.pnas.org\/preview_site\/misc\/userlicense.xhtml"}],"funder":[{"DOI":"10.13039\/100005725","name":"CHDI Foundation","doi-asserted-by":"publisher","award":["A-3267"],"award-info":[{"award-number":["A-3267"]}],"id":[{"id":"10.13039\/100005725","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100000304","name":"Parkinson's UK","doi-asserted-by":"publisher","award":["G-1203"],"award-info":[{"award-number":["G-1203"]}],"id":[{"id":"10.13039\/501100000304","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000065","name":"HHS | NIH | National Institute of Neurological Disorders and Stroke","doi-asserted-by":"publisher","award":["NS057715"],"award-info":[{"award-number":["NS057715"]}],"id":[{"id":"10.13039\/100000065","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["www.pnas.org"],"crossmark-restriction":true},"short-container-title":["Proc. Natl. Acad. Sci. U.S.A."],"published-print":{"date-parts":[[2016,5,10]]},"abstract":"<jats:title>Significance<\/jats:title>\n                  <jats:p>Neurodegenerative diseases such as Alzheimer\u2019s (AD), Parkinson\u2019s (PD), and Huntington\u2019s (HD) present a significant and increasing burden on society. Perturbations in the kynurenine pathway (KP) of tryptophan degradation have been linked to the pathogenesis of these disorders, and thus manipulation of this pathway may have therapeutic relevance. Here we show that genetic inhibition of two KP enzymes\u2014kynurenine-3-monooxygenase and tryptophan-2,3-dioxygenase (TDO)\u2014improved neurodegeneration and other disease symptoms in fruit fly models of AD, PD, and HD, and that alterations in levels of neuroactive KP metabolites likely underlie the beneficial effects. Furthermore, we find that inhibition of TDO using a drug-like compound reverses several disease phenotypes, underscoring the therapeutic promise of targeting this pathway in neurodegenerative disease.<\/jats:p>","DOI":"10.1073\/pnas.1604453113","type":"journal-article","created":{"date-parts":[[2016,4,26]],"date-time":"2016-04-26T00:24:39Z","timestamp":1461630279000},"page":"5435-5440","update-policy":"https:\/\/doi.org\/10.1073\/pnas.cm10313","source":"Crossref","is-referenced-by-count":139,"title":["Tryptophan-2,3-dioxygenase (TDO) inhibition ameliorates neurodegeneration by modulation of kynurenine pathway metabolites"],"prefix":"10.1073","volume":"113","author":[{"given":"Carlo","family":"Breda","sequence":"first","affiliation":[{"name":"Department of Genetics, University of Leicester, Leicester LE1 7RH, United Kingdom;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Korrapati V.","family":"Sathyasaikumar","sequence":"additional","affiliation":[{"name":"Maryland Psychiatric Research Center, Department of Psychiatry, University of Maryland School of Medicine, Baltimore, MD 21228"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shama","family":"Sograte Idrissi","sequence":"additional","affiliation":[{"name":"Department of Genetics, University of Leicester, Leicester LE1 7RH, United Kingdom;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Francesca M.","family":"Notarangelo","sequence":"additional","affiliation":[{"name":"Maryland Psychiatric Research Center, Department of Psychiatry, University of Maryland School of Medicine, Baltimore, MD 21228"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jasper G.","family":"Estranero","sequence":"additional","affiliation":[{"name":"Department of Genetics, University of Leicester, Leicester LE1 7RH, United Kingdom;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gareth G. L.","family":"Moore","sequence":"additional","affiliation":[{"name":"Department of Genetics, University of Leicester, Leicester LE1 7RH, United Kingdom;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Edward W.","family":"Green","sequence":"additional","affiliation":[{"name":"Department of Genetics, University of Leicester, Leicester LE1 7RH, United Kingdom;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Charalambos P.","family":"Kyriacou","sequence":"additional","affiliation":[{"name":"Department of Genetics, University of Leicester, Leicester LE1 7RH, United Kingdom;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Robert","family":"Schwarcz","sequence":"additional","affiliation":[{"name":"Maryland Psychiatric Research Center, Department of Psychiatry, University of Maryland School of Medicine, Baltimore, MD 21228"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Flaviano","family":"Giorgini","sequence":"additional","affiliation":[{"name":"Department of Genetics, University of Leicester, Leicester LE1 7RH, United Kingdom;"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"341","published-online":{"date-parts":[[2016,4,25]]},"reference":[{"key":"e_1_3_3_1_2","doi-asserted-by":"publisher","DOI":"10.1007\/s00109-013-1046-9"},{"key":"e_1_3_3_2_2","doi-asserted-by":"publisher","DOI":"10.2174\/187152710793237430"},{"key":"e_1_3_3_3_2","doi-asserted-by":"publisher","DOI":"10.1016\/0014-2999(81)90587-2"},{"key":"e_1_3_3_4_2","doi-asserted-by":"publisher","DOI":"10.1126\/science.6849138"},{"key":"e_1_3_3_5_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.93.22.12553"},{"key":"e_1_3_3_6_2","doi-asserted-by":"publisher","DOI":"10.1046\/j.1471-4159.1998.70010299.x"},{"key":"e_1_3_3_7_2","doi-asserted-by":"publisher","DOI":"10.1007\/978-1-4615-4709-9_50"},{"key":"e_1_3_3_8_2","doi-asserted-by":"publisher","DOI":"10.1016\/0304-3940(84)90050-8"},{"key":"e_1_3_3_9_2","doi-asserted-by":"publisher","DOI":"10.1046\/j.0953-816x.2001.01592.x"},{"key":"e_1_3_3_10_2","doi-asserted-by":"publisher","DOI":"10.1523\/JNEUROSCI.21-19-07463.2001"},{"key":"e_1_3_3_11_2","doi-asserted-by":"publisher","DOI":"10.1016\/0006-8993(82)91048-4"},{"key":"e_1_3_3_12_2","doi-asserted-by":"publisher","DOI":"10.1007\/978-1-4615-4709-9_49"},{"key":"e_1_3_3_13_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.ntt.2011.07.002"},{"key":"e_1_3_3_14_2","doi-asserted-by":"publisher","DOI":"10.1038\/nrn3257"},{"key":"e_1_3_3_15_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.nbd.2004.07.006"},{"key":"e_1_3_3_16_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.nbd.2006.02.011"},{"key":"e_1_3_3_17_2","doi-asserted-by":"publisher","DOI":"10.1016\/0022-510X(94)00280-2"},{"key":"e_1_3_3_18_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.neuint.2006.08.012"},{"key":"e_1_3_3_19_2","doi-asserted-by":"publisher","DOI":"10.1093\/brain\/115.5.1249"},{"key":"e_1_3_3_20_2","doi-asserted-by":"publisher","DOI":"10.1007\/s00401-006-0086-4"},{"key":"e_1_3_3_21_2","doi-asserted-by":"publisher","DOI":"10.1212\/WNL.42.9.1702"},{"key":"e_1_3_3_22_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.cub.2011.04.028"},{"key":"e_1_3_3_23_2","doi-asserted-by":"publisher","DOI":"10.4161\/fly.19999"},{"key":"e_1_3_3_24_2","doi-asserted-by":"publisher","DOI":"10.1017\/S0016672300029402"},{"key":"e_1_3_3_25_2","doi-asserted-by":"publisher","DOI":"10.1007\/s007020070080"},{"key":"e_1_3_3_26_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1203083109"},{"key":"e_1_3_3_27_2","doi-asserted-by":"publisher","DOI":"10.1038\/35099568"},{"key":"e_1_3_3_28_2","doi-asserted-by":"publisher","DOI":"10.1111\/j.1471-4159.1989.tb09218.x"},{"key":"e_1_3_3_29_2","doi-asserted-by":"publisher","DOI":"10.1016\/0304-3940(90)90410-B"},{"key":"e_1_3_3_30_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0065-2806(08)60130-7"},{"key":"e_1_3_3_31_2","doi-asserted-by":"publisher","DOI":"10.1038\/35006074"},{"key":"e_1_3_3_32_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0006-291X(02)00430-8"},{"key":"e_1_3_3_33_2","doi-asserted-by":"publisher","DOI":"10.1038\/nn0901-887"},{"key":"e_1_3_3_34_2","doi-asserted-by":"publisher","DOI":"10.3109\/01677063.2010.514367"},{"key":"e_1_3_3_35_2","doi-asserted-by":"publisher","DOI":"10.1093\/hmg\/ddu521"},{"key":"e_1_3_3_36_2","doi-asserted-by":"publisher","DOI":"10.1016\/0006-2952(95)00006-L"},{"key":"e_1_3_3_37_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.semcdb.2015.03.002"},{"key":"e_1_3_3_38_2","doi-asserted-by":"publisher","DOI":"10.1093\/hmg\/ddp527"},{"key":"e_1_3_3_39_2","doi-asserted-by":"crossref","first-page":"1416","DOI":"10.1111\/j.1471-4159.2010.06675.x","article-title":"Dysfunctional kynurenine pathway metabolism in the R6\/2 mouse model of Huntington\u2019s disease","volume":"113","author":"Sathyasaikumar KV","year":"2010","unstructured":"KV Sathyasaikumar, , Dysfunctional kynurenine pathway metabolism in the R6\/2 mouse model of Huntington\u2019s disease. J Neurochem 113, 1416\u20131425 (2010).","journal-title":"J Neurochem"},{"key":"e_1_3_3_40_2","doi-asserted-by":"publisher","DOI":"10.1016\/0014-5793(93)81387-F"},{"key":"e_1_3_3_41_2","doi-asserted-by":"publisher","DOI":"10.1007\/s11055-008-0052-9"},{"key":"e_1_3_3_42_2","doi-asserted-by":"publisher","DOI":"10.1111\/j.1474-9726.2011.00762.x"},{"key":"e_1_3_3_43_2","doi-asserted-by":"publisher","DOI":"10.33549\/physiolres.931049"},{"key":"e_1_3_3_44_2","doi-asserted-by":"publisher","DOI":"10.1046\/j.1460-9568.1999.00806.x"},{"key":"e_1_3_3_45_2","doi-asserted-by":"publisher","DOI":"10.1002\/ana.24406"},{"key":"e_1_3_3_46_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.mod.2015.06.002"},{"key":"e_1_3_3_47_2","doi-asserted-by":"publisher","DOI":"10.4161\/fly.5.4.18414"},{"key":"e_1_3_3_48_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2011.05.020"},{"key":"e_1_3_3_49_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.ejmech.2011.09.042"},{"key":"e_1_3_3_50_2","doi-asserted-by":"publisher","DOI":"10.1021\/jm2006782"},{"key":"e_1_3_3_51_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.jsb.2013.01.002"},{"key":"e_1_3_3_52_2","doi-asserted-by":"publisher","DOI":"10.1038\/nature12039"},{"key":"e_1_3_3_53_2","doi-asserted-by":"publisher","DOI":"10.1038\/nmeth.2856"},{"key":"e_1_3_3_54_2","doi-asserted-by":"publisher","DOI":"10.1101\/gr.1276503"},{"key":"e_1_3_3_55_2","doi-asserted-by":"publisher","DOI":"10.1534\/genetics.110.119917"},{"key":"e_1_3_3_56_2","doi-asserted-by":"publisher","DOI":"10.1038\/ng.101"}],"container-title":["Proceedings of the National Academy of Sciences"],"original-title":[],"language":"en","link":[{"URL":"http:\/\/www.pnas.org\/syndication\/doi\/10.1073\/pnas.1604453113","content-type":"unspecified","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/pnas.org\/doi\/pdf\/10.1073\/pnas.1604453113","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2024,6,15]],"date-time":"2024-06-15T19:38:54Z","timestamp":1718480334000},"score":1,"resource":{"primary":{"URL":"https:\/\/pnas.org\/doi\/full\/10.1073\/pnas.1604453113"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2016,4,25]]},"references-count":56,"journal-issue":{"issue":"19","published-print":{"date-parts":[[2016,5,10]]}},"alternative-id":["10.1073\/pnas.1604453113"],"URL":"https:\/\/doi.org\/10.1073\/pnas.1604453113","relation":{},"ISSN":["0027-8424","1091-6490"],"issn-type":[{"value":"0027-8424","type":"print"},{"value":"1091-6490","type":"electronic"}],"subject":[],"published":{"date-parts":[[2016,4,25]]},"assertion":[{"value":"2016-04-25","order":2,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}]}}